Astrocytic noncanonical WNT5B signaling modulates extracellular matrix remodeling and neuropathology in Huntington's disease.

ABSTRACT: Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by a triad of behavioral symptoms: involuntary movement, emotional change, and cognitive dysfunction. Although alterations in WNT signaling have been reported in HD, its precise role in pathogenesis remains unclear. In this study, we found that astrocytic WNT5B mRNA and protein levels are elevated in the striatum of both HD patients and HD model mice. The noncanonical WNT5B signaling pathway induced sustained expression of matrix metallopeptidase 14 (MMP14), an extracellular matrix (ECM)-degrading enzyme, via activation of the NFATc2 transcription factor in both human and primary mouse astrocytes. Robust upregulation of MMP14 led to ECM degradation, medium spiny neuron (MSN) damage, and increased mutant huntingti

SUBMITTER: Nguyen PTT 

PROVIDER: S-EPMC12812802 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature